Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells

Shira Yanovsky-Dagan; Michal Avitzour; Gheona Altarescu; Paul Renbaum; Talia Eldar-Geva; Oshrat Schonberger; Stella Mitrani-Rosenbaum; Ephrat Levy-Lahad; Ramon Y. Birnbaum; Lior Gepstein; Silvina Epsztejn-Litman; Rachel Eiges

doi:10.1016/j.stemcr.2015.06.003

Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells

Shira Yanovsky-Dagan, Michal Avitzour, Gheona Altarescu, Paul Renbaum, Talia Eldar-Geva, Oshrat Schonberger, Stella Mitrani-Rosenbaum, Ephrat Levy-Lahad, Ramon Y. Birnbaum, Lior Gepstein, Silvina Epsztejn-Litman, Rachel Eiges

Ben-Gurion University of the Negev, Technion - Israel Institute of Technology

Research output: Contribution to journal › Article › peer-review

Abstract

CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation.

Original language	American English
Pages (from-to)	221-231
Number of pages	11
Journal	Stem Cell Reports
Volume	5
Issue number	2
DOIs	https://doi.org/10.1016/j.stemcr.2015.06.003
State	Published - 1 Jan 2015

All Science Journal Classification (ASJC) codes

Genetics
Biochemistry
Cell Biology
Developmental Biology

Access to Document

10.1016/j.stemcr.2015.06.003

Cite this

Yanovsky-Dagan, S., Avitzour, M., Altarescu, G., Renbaum, P., Eldar-Geva, T., Schonberger, O., Mitrani-Rosenbaum, S., Levy-Lahad, E., Birnbaum, R. Y., Gepstein, L., Epsztejn-Litman, S., & Eiges, R. (2015). Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells. Stem Cell Reports, 5(2), 221-231. https://doi.org/10.1016/j.stemcr.2015.06.003

@article{41b1a634748e42cd8783fc34c92da77f,

title = "Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells",

abstract = "CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation.",

author = "Shira Yanovsky-Dagan and Michal Avitzour and Gheona Altarescu and Paul Renbaum and Talia Eldar-Geva and Oshrat Schonberger and Stella Mitrani-Rosenbaum and Ephrat Levy-Lahad and Birnbaum, {Ramon Y.} and Lior Gepstein and Silvina Epsztejn-Litman and Rachel Eiges",

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

month = jan,

day = "1",

doi = "10.1016/j.stemcr.2015.06.003",

language = "American English",

volume = "5",

pages = "221--231",

journal = "Stem Cell Reports",

issn = "2213-6711",

publisher = "Cell Press",

number = "2",

}

Yanovsky-Dagan, S, Avitzour, M, Altarescu, G, Renbaum, P, Eldar-Geva, T, Schonberger, O, Mitrani-Rosenbaum, S, Levy-Lahad, E, Birnbaum, RY, Gepstein, L, Epsztejn-Litman, S & Eiges, R 2015, 'Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells', Stem Cell Reports, vol. 5, no. 2, pp. 221-231. https://doi.org/10.1016/j.stemcr.2015.06.003

TY - JOUR

T1 - Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells

AU - Yanovsky-Dagan, Shira

AU - Avitzour, Michal

AU - Altarescu, Gheona

AU - Renbaum, Paul

AU - Eldar-Geva, Talia

AU - Schonberger, Oshrat

AU - Mitrani-Rosenbaum, Stella

AU - Levy-Lahad, Ephrat

AU - Birnbaum, Ramon Y.

AU - Gepstein, Lior

AU - Epsztejn-Litman, Silvina

AU - Eiges, Rachel

PY - 2015/1/1

Y1 - 2015/1/1

N2 - CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation.

AB - CTG repeat expansion in DMPK, the cause of myotonic dystrophy type 1 (DM1), frequently results in hypermethylation and reduced SIX5 expression. The contribution of hypermethylation to disease pathogenesis and the precise mechanism by which SIX5 expression is reduced are unknown. Using 14 different DM1-affected human embryonic stem cell (hESC) lines, we characterized a differentially methylated region (DMR) near the CTGs. This DMR undergoes hypermethylation as a function of expansion size in a way that is specific to undifferentiated cells and is associated with reduced SIX5 expression. Using functional assays, we provide evidence for regulatory activity of the DMR, which is lost by hypermethylation and may contribute to DM1 pathogenesis by causing SIX5 haplo-insufficiency. This study highlights the power of hESCs in disease modeling and describes a DMR that functions both as an exon coding sequence and as a regulatory element whose activity is epigenetically hampered by a heritable mutation.

UR - http://www.scopus.com/inward/record.url?scp=84954164925&partnerID=8YFLogxK

U2 - 10.1016/j.stemcr.2015.06.003

DO - 10.1016/j.stemcr.2015.06.003

M3 - Article

C2 - 26190529

SN - 2213-6711

VL - 5

SP - 221

EP - 231

JO - Stem Cell Reports

JF - Stem Cell Reports

IS - 2

ER -

Uncovering the Role of Hypermethylation by CTG Expansion in Myotonic Dystrophy Type 1 Using Mutant Human Embryonic Stem Cells

Abstract

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Cite this